Patent EA-002819-B1 (EA)
Title: Cyclic peptide compound and use thereof, bicyclopeptide compound, peptide compound and use thereof, pharmaceutical composition
Inventor: CONDON STEPHEN M
IPC: C07K7/64
Filed: 1998-05-13
Abstract: 1. A cyclic peptide compound of formula X-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-Y or a pharmaceutically acceptable salt or prodrug precursor thereof wherein (a) R1a-Ao-A1-A2-A3-A4-A5-A6-A7-A8-A9-, (b) R1a-A2-A3-A4-A5-A6-A7-A8-A9-, (c) R1b-A3-A4-A5-A6-A7-A8-A9-, (d) R1a-A4-A5-A6-A7-A8-A9-, (e) R1a-A5-A6-A7-A8-A9-, (f) R1a-A6-A7-A8-A9-, (g) R1a-A7-A8-A9-, (h) R1a-A8-A9-, (i) R1a-A9-, (j) R1a-; Y is selected from the group consisting of (a) -R3, (b) -A28-R3, (c) -A28-A29-R3, (d) -A8-A29-A30-R3, (e) -A28-A29-A30-A31-R3, (f) -A28-A29-A30-A31-A32-R3, (g) -A28-A29-A30-A31-A32-A33-R3, (h) -A28-A29-A30-A31-A32-A33-A34-R3; R1a is H, aliphatic hydrocarbon group, which can be straight or branched and has from about 1 to about 20 carbon atoms in chain (alkyl), aromatic monocyclic or polycyclic ring system having from about 6 to about 14 (preferably from about 6 to about 10) carbon atoms bonded to main molecular part by means of bivalent group, obtained from saturated hydrocarbon with straight or branched chain by removal of two hydrogen atoms (aralkyl) or -COR2; R1b is R1a or a group of formula:   or   R2 is alkyl, aliphatic hydrocarbon group, which comprises carbon-carbon double bond and which can be straight or branched and has from about 2 to about 20 carbon atoms in chain (alkenyl), aliphatic hydrocarbon group, which comprises carbon-carbon triple bond and which can be straight or branched, having from about 2 to about 20 carbon atoms in chain (alkynyl), aromatic monocyclic or polycyclic ring system having from about 6 to about 14 (preferably from about 6 to about 10) carbon atoms (aryl); or aralkyl; R3 is a group of formula A35-OR4 or A35-NR4R5; R4 and R5 are independently H or aliphatic hydrocarbon group, which can be straight or branched and has from about 1 to about 4 carbon atoms in chain (lower alkyl); R6 and R9 are independently H or alkyl; R7 is alkyl; R8 is H, alkyl or COR2; R10 is H or halogen; R11 is alkyl or aralkyl; A0 is absent or a peptide of from one to six amino acid residues; A1 is Ser, Ala, Gly or D-Pro, or an equivalent amino acid thereof; A2 is Ala, Val or Gly, or an equivalent amino acid thereof; A3 is Ala, Ser, Gly or D-Pro, or an equivalent amino acid thereof; A4 is Glu, Ala or Gly, or an equivalent amino acid thereof; A5 is Ile, His, Ala or Gly, or an equivalent amino acid thereof; A6 is Ala, Gln, Gly or D-Pro, or an equivalent amino acid thereof; A7 is Ala, Leu, Gly, or an equivalent amino acid thereof; A8 is Leu, Nle, Gly or D-Pro, or an equivalent amino acid thereof; A9 is His, Ala, D-Pro or Gly, or an equivalent amino acid thereof; A10 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, D-Pro, -NHCH(CH2)mNH2)CO- or -NHCH-[(CH2)n CO2H]-CO-; A11 is Ala, Gly, Leu or Lys, or an equivalent amino acid thereof; A12 is Ala or Gly, or an equivalent amino acid thereof; A13 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, -NHCH(CH2)m NH2)CO- or -NHCH[(CH2)n CO2H]CO-; A14 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, His, Lys, Orn, Ser, Thr, D-Pro, -NHCH(CH2)m NH2)CO- or -NHCH-[(CH2)n CO2H]CO-; A15 is Ala, Gly, Ile, D-Pro or Leu, or an equivalent amino acid thereof; A16 is Asn, Ala, Gly, D-Pro or Gln, or an equivalent amino acid thereof; A17 is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, D-Pro, -NHCH(CH2)m NH2)CO- or -NHCH[(CH2)n CO2H]CO-; A18 is Asp, Cys, homo-Cys, Glu, His, Leu, Lys, Orn, Nle, Ser, Thr, -NHCH(CH2)m NH2)CO- or -NHCH[(CH2)n CO2H]CO-; A19 is Arg or Glu, or an equivalent amino acid thereof; A20 is Arg or an equivalent amino acid thereof; A21 is Arg, Asp, Cys, homo-Cys, Glu, Lys, Orn, Ser, Thr, Val, -NHCH(CH2)m NH2)CO- or -NHCH[(CH2)n CO2H]CO-; A22 is Asp, Cys, homo-Cys, Glu, His, Lys, Orn, Phe, Ser, Thr, -NHCH(CH2)m NH2)CO- or -NHCH[(CH2)n CO2H]CO-; A23 is Leu, Phe or Trp, or an equivalent amino acid thereof; A24 is Leu or an equivalent amino acid thereof; A25 is Arg, Asp, Cys, homo-Cys, Glu, His, Lys, Orn, D-Pro, Ser, Thr, -NHCH(CH2)m NH2)CO- or --NHCH[(CH2)n CO2H]CO-; A26 is Asp, Cys, homo-Cys, Glu, His, Lys, Orn, Ser, Thr, -NHCH(CH2)m NH2)CO or -NHCH[(CH2)n CO2H]CO-; A27 is Leu or Lys, or an equivalent amino acid thereof; A28 is Ile or Leu, or an equivalent amino acid thereof; A29 is Ala, Asp, Cys, homo-Cys, Glu, Gln, Lys, Orn, Ser, Thr, -NHCH(CH2)m NH2)CO- or -NHCH[(CH2)n CO2H]CO-; A30 is Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, -NHCH(CH2)m NH2)CO- or -NHCH[(CH2)n CO2H]CO-; m is 1, 2 or 3; n is 3 or 4; A31 is Ile, Leu or Val, or an equivalent amino acid thereof; A32 is His, or an equivalent amino acid thereof; A33 is Asn or Thr, or an equivalent amino acid thereof r; and A34 is Ala or Phe, or an equivalent amino acid thereof; A35 is absent or a peptide of from 1 to 4 amino acids; and the side chains of at least one of the following pairs of amino acid residues, A10 and A14, A13 and A17, A14 and A18, A17 and A21, A18 and A22, A21, and A25, A25 and A29 and A26 and A30 are linked through an amide, ester, disulfide or lanthionine bond to form a bridge, and the side chain of each of A10, A13, A14, A17, A18, A21, A22, A25, A26, A29, and A30, contributes, at most, to the formation of a single bridge; provided that when the side chains of A13 and A17 or A26 and A30 are linked through an amide, disulfide or lanthionine bond to form a bridge, then the side chains of at least one of the following pairs of amino acid residues, A10 and A14, A14 and A18, A17 and A21, A18 and A22, A21, and A25 and A25 and A29 are also linked through an amide, ester, disulfide or lanthionine bond. 2. A peptide compound according to Claim 1, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein the bridge formed from the side chains of one pair of amino acid residues is non-overlapping with a bridge formed between the side chains of another pair of amino acid residues. 3. A peptide compound according to Claim 2, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein A10 is Ala, Asn, Asp, Gly or Lys; A13 is Ala, Gly or Lys; A14 is Ala, Asp, Gly, His, Lys or Ser; A17 is Ala, Asp, Gly, Lys or Ser; A18 is Asp, Leu, Lys, Orn or Nle; A21 is Arg, Asp, Lys or Val; A22 is Asp, Glu, Lys, Orn or Phe; A25 is Arg, Asp, Glu, His or Lys; A26 is His or Lys; A29 is Ala, Asp, Glu or Gln; A30 is Asp, Glu or Lys; and the side chains of at least one of the following pairs of amino acid residues, A10 and A14, A13 and A17, A14 and A18, A17 and A21, A18 and A22, A21, and A25, A25 and A29 and A26 and A30 are linked through an amide bond to form a bridge, and the side chain of each of A10, A13, A14, A17, A18, A21, A22, A25, A26, A29, and A30 contributes, at most, to the formation of a single bridge; provided (a) that when the side chains of A13 and A17 are linked through an amide bond to form a bridge, then the side chains of at least one of A18 and A22, A21, and A25, and A25 and A29 are also linked through an amide bond; (b) that when the side chains of A26 and A30 are linked through an amide bond to form a bridge, then the side chains of at least one of A10 and A14, A14 and A18, A17 and A21, A18 and A22 and A21, and A25 are also linked through an amide bond; and (c) that when the side chains of A13 and A17 and A26 and A30 are linked through an amide bond to form a bridge, then the side chains of A18 and A22 or A21 and A25 are also linked through an amide bond. 4. A peptide compound according to Claim 3, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein R1a is H and Y is NH2. 5. A peptide compound according to Claim 4, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein X is (a) R1a-A1-A2-A3-A4-A5-A6-A7-A8-A9-, (b) R1a-A2-A3-A4-A5-A6-A7-A8-A9- or (c) R1a-A3-A4-A5-A6-A7-A8-A9-. 6. A peptide compound according to Claim 5, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein A1 is Ala, Gly or D-Pro; A8 is Nle and A27 is Leu. 7. A peptide compound according to Claim 6, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein (i) the side chains of A10 and A14 are linked through an amide bond to form a bridge; (ii) the side chains of A14 and A18 are linked through an amide bond to form a bridge; (iii) the side chains of A17 and A21 are linked through an amide bond to form a bridge; (iv) the side chains of A18 and A22 are linked through an amid bond to form a bridge; (v) the side chains of A21 and A25 are linked through an amide bond to form a bridge; or (vi) the side chains of A25 and A29 are linked through an amide bond to form a bridge. 8. A peptide compound according to Claim 7, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein A10 is Asp or Lys; A13 is Lys; A14 is Asp or Lys; A17 is Asp or Ser; A18 is Nle; A21 is Arg or Val; A22 is Glu or Phe; A25 is Arg or His: A26 is Lys or His, A29 is Ala or Gln; and A30 is Asp or Glu; and the side-chains of A10 and A14 are linked through an amide bond to form a bridge. 9. A peptide compound according to Claim 7, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is Asp or Lys; A17 is Asp or Ser; A18 is Nle; A21 is Arg or Val; A22 is Glu or Phe; A25 is Arg or His; A26 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu; and the side chains of A14 and A18 are linked through an amide bond to form a bridge. 10. A peptide compound according to Claim 7, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Asp or Lys; A18 is Nle; A21 is Asp or Lys; A22 is Glu or Phe; A25 is Arg or His; A26 is His or Lys; A29 is Ala or Gln; and A30 is Asp or Glu; and the side chains of A17 and A21 are linked through an amide bond to form a bridge. 11. A peptide compound according to Claim 7, or a pharmaceutically acceptable salt or prodrug precursor thereof wherein A10 is Asn or Asp; A13 is Lys; A14 is His or Ser; A17 is Asp or Ser; A18 is Asp, Lys or Orn; A2